Commentary on D-ALBA Study

Dr Ng Chin Hin,
Senior Consultant Haematologist, CFCH
Former Head of Adult Leukaemia Service, National University Cancer Institute, Singapore
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Do we see the arrival of chemotherapy-free treatment for Philadelphia positive acute lymphoblastic leukaemia?
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Philadelphia positive acute lymphoblastic leukaemia (Ph+ALL) has been conventionally regarded as a form of poor risk ALL that requires intensive chemotherapy and allogeneic stem cell transplant (alloSCT). In the pre-TKI (tyrosine kinase inhibitor) era, the overall survival at five years was between 30-40% with alloSCT1..

The introduction of TKI, i.e. Imatinib, Dasatinib and Ponatinib into standard intensive chemotherapy, has improved the outcomes Ph+ALL with or without alloSCT. For example, the 5-year overall survival for imatinib, Dasatinib and ponatinib with HyperCVAD regimen is 43%, 46% and 71% respectively 2-4. Treatment of elderly Ph+ALL remains a significant challenge as most of these patients are unfit for intensive chemotherapy and ineligible for alloSCT. Elderly Ph+ALL who receive Dasatinib with low-intensity chemotherapy may attain up to a 36% long term survival5. However, in clinical practice, many of the older Ph+ALL are unable to tolerate even low-intensity chemotherapy..

Blinatumomab is a bi-specific monoclonal antibody that targets both CD3 (normal T-cells) and CD19 (the B-lymphoblasts). It activates T-cells and brings them near the B-lymphoblasts resulting in the killing of leukemic cells..

The GIMEMA group designed a chemotherapy-free treatment strategy for newly diagnosed Ph+ALL, incorporating Dasatinib with Blinatumomab. Patients received Dasatinib plus steroid during the induction phase (85 days) followed by consolidation phase with five cycles of Blinatumomab..

Dasatinib was also continued during and after the consolidation phase. A total of 63 patients were recruited with a median age of 54 years (range: 24-82). At the end of the induction phase, 98% of those who completed the induction achieved complete haematologic remission. At the end of cycle 4 of Blinatumomab, 81% achieved a molecular response. With a median follow-up of 18 months, the overall survival was 95% while the disease-free survival was 88%. The cumulative incidence of relapse was 8%. Blinatumomab effectively cleared seven patients who developed mutations (6 T315I, 1 E255K) during the induction phase during the consolidation phase..

The combination therapy appeared to be well tolerated with no early death reported. Twenty-four patients eventually underwent alloSCT. Impressively, only one transplant-related mortality (TRM) reported (4%). The authors believed that a prior chemotherapy-free regimen could have contributed to a low TRM..

Though this was a phase 2 single-arm study, the results were overwhelmingly impressive. This could be a new standard of care, especially for older Ph+ALL. A phase 3 randomised study comparing this to the standard TKI plus intensive chemotherapy is eagerly awaited and the results, if positive, could set a new standard of care for Ph+ALL.
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Reference:

1. 1. Preti HA, O’Brien S, Giralt S, Beran M, Pierce S, Kantarjian HM. Philadelphia-chromosome-positive adult acute lymphocytic leukaemia: characteristics, treatment results, and prognosis in 41 patients. Am J Med. 1994 Jul;97(1):60-5
   2. Daver N, Thomas D, Ravandi F et al. Final report of a phase II study of imatinib mesylate with hyper-CVAD for the front-line treatment of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia. Haematologica. 2015 May;100(5):653-61.
   3. Ravandi F, O’Brien SM, Cortes JE et al. Long-term follow-up of a phase 2 study of chemotherapy plus Dasatinib for the initial treatment of patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia. Cancer. 2015 Dec 1;121(23):4158-64.
   4. Jabbour E, Short NJ, Ravandi F, et al. Combination of hyper-CVAD with ponatinib as first-line therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia: long-term follow-up of a single-centre, phase 2 study. Lancet Haematol. 2018 Dec;5(12):e618-e627
   5. Rousselot P, Coudé MM, Gokbuget N et al. European Working Group on Adult ALL (EWALL) group. Dasatinib and low-intensity chemotherapy in elderly patients with Philadelphia chromosome-positive ALL. Blood. 2016 Aug 11;128(6):774-82
      Foà R, Bassan R, Vitale A, et al. GIMEMA Investigators. Dasatinib-Blinatumomab for Ph-Positive Acute Lymphoblastic Leukemia in Adults. N Engl J Med. 2020 Oct 22;383(17):1613-1623
      

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